The present invention relates novel amides. Compounds of the present invention have been biologically tested towards the adenosine receptors and have surprisingly been shown to be capable of binding to the adenosine receptors, having activity in functional assays, as well as showing effect in vivo.
Compounds of the present invention are either agonists or antagonists of a specific adenosine receptor or a number of adenosine receptors, more specifically at the adenosine A2A receptor.
There are today a large amount of documents in the literature describing the present knowledge on adenosine and the adenosine receptors, a few examples are given below.
The adenosine receptors belong to the class of G-protein coupled receptors, also known as seven transmembrane receptors, which are all built from a single polypeptide forming 7 transmembrane domains. As the name indicates, adenosine is a naturally occurring endogenous ligand, which upon activation of the receptors initiates a signal transduction mechanism. There are currently four subtypes of adenosine receptor identified; A1, A2A, A2B and A3. (Jacobson, et al., Adenosine receptors as therapeutic targets. Nat Rev Drug Discov 5, 247-64, 2006). All the receptors have a unique pharmacological profile and tissue distribution and there are growing evidence of their influence in a number of conditions such as cerebral and cardiac ischaemic diseases, sleeping disorders, cancer, immune and inflammatory disorders, Alzheimer's disease, Parkinson's disease Huntingtons's disease, neuroprotection, schizophrenia, anxiety, pain, respiration deficits, depression, drug abuse (amphetamine, cocaine, opioids, ethanol, nicotine, cannabinoids), or against asthma, allergic responses, hypoxia, ischaemia, seizure, and substance abuse, sedatives, muscle relaxants, antipsychotics, antiepileptics, anticonvulsants and cardiaprotective agents for disorders such as coronary artery disease and heart failure. The adenosine A2, has been shown to have a crucial role in the modulation of prolonged systemic inflammatory responses (Ohta, et al., Role of G-protein-coupled adenosine receptors in downregulation of inflammation and protection from tissue damage. Nature 414, 916-20, 2001). More specifically the A2A receptor has been investigated in vivo for treatment of sepsis (Sullivan, et al., A2, adenosine receptor activation improves survival in mouse models of endotoxemia and sepsis. J Infect D is 189, 1897-904, 2004), inflammatory bowel disease (Odashima, et al. Activation of A2A adenosine receptor attenuates intestinal inflammation in animal models of inflammatory bowel disease. Gastroenterology 129, 26-33, 2005), reducing skin pressure, ulcer formation and inflammation (Peirce, et al., Selective A2A adenosine receptor activation reduces skin pressure ulcer formation and inflammation. Am J Physiol Heart Circ Physiol 281, H67-74, 2001), improved wound healing (Montesinos, et al., Adenosine promotes wound healing and mediates angiogenesis in response to tissue injury via occupancy of A2A receptors. Am J Pathol 160, 2009-18, 2002), as well as been implicated as a route for arthritis treatment (Hasko, et al., Adenosine: an endogenous regulator of innate immunity, Trends Immunol 25, 33-9, 2004).
Hence, after more than three decades of research of the adenosine receptors, a variety of physiological actions have been identified that are thought to be mediated by the distinct subtypes of each receptor. In many cases, however, it is still not entirely clear which of the subtypes that is responsible for the effect
The compounds in the present application are structurally different from the previously published adenosine agonists and antagonists, e.g. WO06091936, WO06091898, WO06091897, WO06091896, WO05097140, WO04063177, WO06028618, WO030186926, WO04105755, WO04063177, and reviewed in Jacobson et al., (Adenosine as receptor targets, Nature reviews, 5, 247-264, 2006). Most of the applications are related to modifications of adenosine itself, which makes the observed effects of the novel compounds are unexpected.